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Medicinal Chemistry - Winter > 16, 17 - Cancer > Flashcards

16, 17 - Cancer Flashcards

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1
Q

Majority of antitumour antibiotics are isolated and discovered from ______

A

Microbial fermentations

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2
Q

What are bleomycins? What is the MOA?

A
  • Cytotoxic glycopeptide antibiotics
  • Believed that bleomycin chelates metal ions (mostly Fe2+ and Cu2+), producing a pseudoenzyme that reacts w/ oxygen to produce free radicals that cause DNA strand breaks, ultimately leading to cytotoxic event
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3
Q

What determines therapeutic efficacy of bleomycins?

A
  • Dose-dependent pneumonitis (lung toxicity)

- May be related to absence of bleomycin hydrolase in the lungs of some px

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4
Q

Describe the bleomycin DNA strand break model

A
  • dsDNA cleavage by a single bleomycin molecule requires bleomycin reactivation and reorganization during or after cleavage of first strand of DNA
  • Key to reorganization is the linker and flexibility of the bithiazole tail that is bound by partial intercalation
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5
Q

What form of bleomycin is responsible for initiating DNA damage? How is this formed?

A
  • Bleomycin binding to Fe2+, followed by oxygen binding and reduction by a reductant
  • This intermediate is responsible
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6
Q

What is required for activated bleomycin to be generated?

A
  • Bleomycin-Cu(2) must be reduced to bleomycin-Cu(1) intracellularly
  • Cu(1) must dissociate from bleomycin and Fe(2) must bind
  • Once Fe(2) is bound, the chemistry to form activated bleomycin ensues
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7
Q

Describe the structure of anthracyclins

A

Planar oxidized anthracene ring fused to a cyclohexane ring that is attached via glycosidic linkage to amino sugar

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8
Q

What is the general mechanism of anthracyclins?

A

Intercalation followed by inhibition of topoisomerase 2 leading to DNA strand breakage and apoptosis

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9
Q

Which are the 5 accepted anthracyclins?

A
  • Doxorubicin
  • Daunorubicin
  • Epirubicin
  • Valrubicin
  • Idarubicin
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10
Q

What is the MOA of doxorubicin?

A
  • Stabilizes topoisomerase 2 complex after it has broken the DNA chain for replication, preventing DNA double helix from being resealed
  • Generation of free radicals and resulting oxidative stress causing cell death and membrane damage and DNA strand breaks
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11
Q

How does doxorubicin enter a cell?

A
  • Diffusion

- Via the SLC transporter

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12
Q

Why is the use of doxorubicin limited? What causes this?

A
  • Cardiotoxicity that leads to congestive heart failure (above 350 mg/m^2)
  • Caused by redox cycling (doxorubicin is a quinone that is reduced to a semiquinone free radical, which reacts w/ oxygen to reform quinone)
  • Also doxorubicin forms a strong complex w/ Fe3+, which can be reduced to Fe2+ complex, which then forms a hydroxyl radical that is extremely reactive and damaging to cell membranes and proteins
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13
Q

What is dexrazoxane? What is the MOA?

A
  • Cardioprotective agent against doxorubicin-induced cardiotoxicity in tx of metastatic breast cancer
  • Crosses cell membranes and hydrolyzed to ADR-925 inside the cell
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14
Q

What are some anticancer drugs that target topoisomerase 2?

A
  • Etoposide
  • Doxorubicin
  • Mitoxantrone
  • Amsacrine
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15
Q

What is the function of DNA topoisomerase 2 in the cell? What does it require to function?

A
  • DNA replication
  • DNA recombination
  • Chromosome condensation/ decondensation
  • Segregation of sister chromatids
  • Requires an ATP cofactor to drive the reaction
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16
Q

What do topoisomerase 2 poisons do?

A
  • Cause single and double strand DNA breaks
  • Increase topoisomerase 2 levels and renders cells hypersensitive
  • Stabilize topoisomerase 2-DNA covalent complexes
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17
Q

When is topoisomerase 2 most highly expressed?

A

When cells are dividing

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18
Q

What do topoisomerase 2 catalytic inhibitors do?

A
  • Don’t cause DNA strand breaks

- Don’t stabilize topoisomerase 2-DNA cleavable complexes

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19
Q

What is the MOA of etoposide and teniposide?

A
  • Topoisomerase 2 inhibitors

- Act in late G2/M phase of cell cycle by preventing cells from entering mitosis

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20
Q

What limits the use of etoposide?

A
  • It causes severe myelosuppression

- May lead to a secondary leukemia several years later (derived from etoposide DNA damage)

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21
Q

What causes etoposide drug resistance?

A

MDR (multidrug resistance) protein being over expressed

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22
Q

What is podophyllotoxin?

A
  • Antimitotic

- Acts by binding to tubulin

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23
Q

What do amsacrine and mitoxantrone work?

A

Inhibit human topoisomerase 2 by inserting into enzyme-mediated DNA cleavage sites

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24
Q

Which drugs are camptothecins? How do they work?

A
  • Topotecan and irinotecan
  • Topoisomerase 1 inhibitors
  • Both have addition of basic amine side chains to increase water solubility
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25
Q

What is the function of topoisomerase enzymes?

A
  • Control supercoiling of DNA, maintaining proper topological state or superhelical tension
  • Topoisomerase 1 causes single strand breaks; topoisomerase 2 causes double strand breaks
26
Q

What is the MOA of camptothecins?

A
  • Bind to DNA-topoisomerase 1 complex after strand cleavage, w/ planar ring structure intercalating w/ DNA, stabilizing cleavable complex, preventing realignment and resealing
  • During DNA replication, stabilized complex leads to double-stranded DNA breaks and cell death
27
Q

What is the effect of dactinomycin?

A
  • Binds non-covalently to double-stranded DNA by intercalation of planar phenoxazone ring between adjacent guanine-cytosine bases, inhibiting DNA function
  • Peptide loops sit in minor groove, providing additional intercalation
28
Q

What are the indications for topotecan and irinotecan?

A
  • Topotecan = metastatic carcinoma of ovaries after failure of initial or subsequent therapy; second line for small cell lung cancer
  • Irinotecan = first line for px w/ metastatic carcinoma of colon or rectum
29
Q

What does mitomycin C do?

A
  • Bio-reductive alkylating agent that can react w/ DNA nucleophiles, following bioactivation (methanol eliminating, aziridine ring opening) to give an electrophilic intermediate
  • Alkylation preferred at GC rich regions of DNA, w/ guanine alkylation at 2-amino group
30
Q

What does alkaloids mean?

A

Natural products containing mostly basic nitrogen atoms, usually has a nitrogen containing ring system as key functional group

31
Q

Describe the structure of Vinca alkaloids

A

Two conjoined groups – catharanthine moiety (indole, azonine, piperidine ring systems) and vindoline moiety (dihydroindole, cyclohexane, pyrrolidine, piperidine)

32
Q

Which drugs are vinca alkaloids?

A
  • Vinblastine
  • Vincristine
  • Vinorelbine
33
Q

What is the effect of vinca alkaloids?

A

Accumulate in cells, bind to tubulin and disrupt formation of mitotic spindle, inhibiting microtubule assembly

34
Q

What is the function of the mitotic spindle?

A
  • Function as cell’s cytoskeleton and maintain cellular shape
  • Involved in movement of chromosome during mitosis and cell signaling
35
Q

What is a concern w/ vinca alkaloids? What is used to fix this?

A
  • Extravasation (leakage of infused substances resulting in tissue destruction)
  • Hyaluronidase promotes re-absorption of tissue fluids
36
Q

What is the effect of taxanes?

A

Bind to tubulin (at a different site than Vinca’s), stabilizing the microtubule and preventing depolymerization, blocking mitosis

37
Q

Which drugs are taxanes?

A

Taxol and taxotere

38
Q

What is the major difference between vinca alkaloids and taxanes?

A
  • Vinca’s (vinblastine) binds on the plus end of of tubulin

- Taxanes (paclitaxel) binds on interior surface

39
Q

What are advantages to epothilones over taxanes?

A

For epothilones, conversion of lactone to lactam offers greater metabolic stability and water solubility

40
Q

When are protein kinase inhibitors used?

A

In combination w/ more traditional chemotherapeutics to achieve better outcomes

41
Q

What are protein kinases important for?

A

Signal transduction, differentiation, growth, regulation and division of cells

42
Q

What is the effect of tyrosine kinase inhibitors?

A

Limit catalytic activity of EGFR

43
Q

Kinase inhibitors mimic ____

A

ATP

44
Q

___ was the first approved kinase inhibitor

A

Imatinib

45
Q

What does imatinib bind to?

A

ATP binding site of the c-Abl tyrosine kinase domain

46
Q

What is the difference between type 1 and type 2 binding of kinase inhibitors?

A
  • Type 1 inhibitors bind to active conformation of the kinase, w/ aspartate residue of DFG motif pointing into ATP-binding pocket
  • Type 2 inhibitors bind and stabilize inactive conformation of kinase w/ the flipped aspartate residue facing outward of binding pocket
47
Q

What is the difference between the kinase inhibitor binding models?

A
  • Type 1 inhibitors have 2 hydrophobic pockets and H-bond to hinge unit in adenine site
  • Type 2 inhibitors have 1 hydrophobic pocket, 1 allosteric pocket, and 2 sites for H-bonds (hinge and allosteric)
48
Q

What is a limitation to tyrosine kinase inhibitors?

A

Long term use results in cardiotoxicity for some

49
Q

What are the mechanisms of cardiotoxicity for tyrosine kinase inhibitors?

A

1) On-target toxicity due to inhibiting intended target
2) Off-target toxicity due to a kinase not intended to be inhibited
3) ATP-binding proteins and other proteins can bind inhibitors

50
Q

What is lapatinib?

A
  • Small molecule tyrosine kinase inhibitor used to treat breast cancers that overexpress HER2
  • Strongly inhibits tyrosine kinase activity of HER2 and EGFR by directly competing w/ ATP
51
Q

What is trastuzumab?

A
  • Humanized antibody used to treat early stage breast cancers that overexpress HER2
  • Binds to extracellular domain of HER2 receptor
  • MOA not well understood; may promote internalization and degradation of the receptor; may also induce immune response to attack the cell, so can be cardiotoxic
52
Q

What is the function of bevacizumab? What is its indication?

A
  • Neutralizes biologic activity of human vascular endothelial growth factor (VEGF)
  • Used to treat metastatic colorectal cancer and others
53
Q

What is the function of cetuximab? What is its indication?

A
  • Binds to human epidermal growth factor receptor (EGFR)

- Used to treat metastatic colorectal carcinoma

54
Q

What is the function of ipilimumab? What is its indication?

A
  • Binds to and blocks human cytotoxic T lymphocyte-associated antigen 4
  • Tx of unresectable or metastatic melanoma
55
Q

What is the function of nivolumab? What is its indication?

A
  • Inhibits T-cell proliferation by binding to programmed cell death protein 1
  • Tx metastatic BRAF V600 wild-type melanoma
56
Q

What is the function of ofatumumab? What is its indication?

A
  • Binds to CD20 molecule leading to cell death

- Tx of px w/ chronic lymphocytic leukemia (CLL)

57
Q

What is the function of panitumumab? What is its indication?

A
  • Binds to human EGFR

- Tx for metastatic colorectal carcinoma

58
Q

What is the function of rituximab? What is its indication?

A
  • Binds to CD20

- Used to tx non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia

59
Q

What is the effect of bortezomib?

A
  • Inhibits proteasome by forming covalent boron-threonine bond at active site
  • Leads to cell cycle arrest and induction of apoptosis
60
Q

What is the function of proteasomes?

A

Degrade unneeded or damaged proteins by proteolysis of peptide bonds

61
Q

Which drugs target the protease activity of the proteasome?

A

Bortezomib and carfilzomib

Medicinal Chemistry - Winter (15 decks)

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